Sox2 Is An Indispensable Transcriptional Regulator During The Embryonic Development Of Mammals. It Is Mainly Involved In The Self-renewal Of Embryonic Stem Cells And The Formation

Part 1 Clinical significance of plasma D-dimer levels in renal involvement of ANCA-associated vasculitis Background:Anti-neutrophil cytoplasmic antibody(ANCA)associated vasculitis(AAV)describes a group of autoimmune diseases characterized by fibrinoid necrosis of small blood vessel with frequent multi-systematic involvement and poor prognosis.Early attention to AAV activity and timely treatment can significantly improve the prognosis.C-reactive protein(CRP)and interleukin-6(IL-6)showed relatively high sensitivity and specificity,and showed relatively limited clinical application.BVAS score is a common tool to evaluate AAV activity,but it is susceptible to subjective factors.Recent studies have found that the risk of venous thromboembolism(VTE)in AAV patients is high and the prognosis is poor.It is particularly important that timely and effective intervention,especially in the first year after the onset of the disease.D-dimer is a specific degradation product produced after the hydrolysis of cross-linked fibrin.It is a marker of secondary hyperfibrinolysisAs a specific degradation product after the hydrolysis of cross-linked fibrin,D-dimer is a marker of secondary hyperfibrinolysis,and its high blood level has been widely used as a biomarker to assess the risk of thromboembolism.In recent years,the role of D-dimer in autoimmune diseases has gradually been in the spotlight.It was reported that D-dimer in synovial fluid and serum of patients with rheumatic arthritis(RA)is significantly increased,and the increased D-dimer level,to a certain extent,reflected the activity degree of disease and assessed the prognosis of patients.There is also evidence that the level of circulating D-dimer is related to the activity of systemic lupus erythematosus(SLE)and the severity of renal damage,which is a new marker for the assessment of SLE activity.Yet whether D-dimer is involved in the pathogenesis of AAV is still unclear.This study retrospectively analyzed 50 patients with AAV renal damage diagnosed by renal biopsy from May 2014 to November 2017 in nephrology department of Xinqiao hospital,Army Medical University.The clinicopathological characteristics of AAV patients with different D-dimer levels were compared,and the clinical significance of D-dimer in AAV was discussed.Method:The clinical and renal pathological data of AAV patients mentioned above were collected.AAV was diagnosed according to the 2012 Chapel Hill Consensus Conference(CHCC)diagnostic criteria for systemic vasculitis.Then AAV patients were divided into two groups using the median plasma D-dimer level(3.17mg/L FEU)as the cut-off point.Then the clinical characters,outcomes of laboratory tests,renal pathology and prognosis of both groups were assessed.The correlation between D-dimer level and other clinical indicators were also analyzed.The diagnostic efficacy of plasma D-dimer,CRP and IL-6 levels in AAV was evaluated by ROC curve.Result:1.C-reactive protein(CRP),interleukin-6(IL-6)level and BVAS scores of high level group were higher than that of low level group(P=0.001,0.015,0.055),24 hours urinary protein,serum albumin were less than low level group(P=0.031,0.006);2.Plasma D-dimer level of AAV patients were positively correlated with BVAS(r=0.322,P=0.022)and CRP(r=0.573,P<0.001),IL-6(r=0.341,P=0.015),TNF-?(r=0.343,P=0.015);3.ROC curve analysis showed that the AUC of plasma D-dimer in evaluating the activity of AAV patients was 0.707,P=0.174,95%CI(0.471,0.942).Serum CRP was 0.700,P=0.198,95%CI(0.491,0.900).IL-6 was 0.633,P=0.381,95%CI(0.463,0.803);4.There was no significant difference in the total number of glomeruli,the percentage of normal glomeruli,and the incidence rate of bulbar sclerosis between the two groups(P> 0.05).Compared with the high level group,the percentage of spheroidal sclerosis was higher in the low level group(P=0.002),and the number of patients with crescent formation was lower(P=0.247).The number and the percentage of patients with cellular crescent formation in high level group were more than those in the low level group(P=0.017;P=0.027).There was no significant difference in the formation of fibrous crescent between the two groups(P> 0.05);5.The plasma D-dimer was used to evaluate the crescents in AAV patients(AUC=0.699,P=0.076,95% CI(0.448,0.951).Stratified analysis showed the AUC of cellular crescents was 0.755,P=0.010,95% CI(0.559,0.952);and the AUC of fibrous crescents was 0.470,P=0.731,95% CI(0.304,0.636).6.Kaplan-Meier survival analysis showed no significant difference in renal cumulative survival between the two groups(P=0.392).Conclusion:1.Plasma D-dimer level of AAV patients was positively correlated with BVAS,CRP,IL-6 and TNF-?;2.Compared with serum CRP and IL-6,the diagnostic efficacy of plasma D-dimer level was higher in the assessment of active AAV patients;3.The level of D-dimer in plasma can indirectly reflect the activity of histopathological injury,especially the formation of cellular crescent,which has certain predictive value.We should pay attention to the risk of thrombosis as well as the activity of pathological tissue.4.Plasma D-dimer is expected to be a marker for the assessment of AAV activity.Part 2 Expression and significance of Sox2 in renal involvement of ANCA-associated vasculitisBackground:Renal impairment,which occurs in more than half of AAV patients,is the main cause of rapid progression of AAV.It presents as pauci-immune crescent nephritis.If not treated in time,rapid and irreversible renal failure can occur in a short period of time,with a one-year mortality of up to 80%.Sox2 is an indispensable transcriptional regulator during the embryonic development of mammals.It is mainly involved in the self-renewal of embryonic stem cells and the formation of endoderm and ectoderm.Studies have shown that Sox2 can reprogram differentiated somatic cells into induced pluripotent stem cells(i PSCs)by co-acting with transcription factors c-Myc,Klf4 and Oct-4,which have the potential of self-renewal and multi-directional differentiation.Sox2 is called molecular rheostat in the process of somatic cell transdifferentiation,and has attracted extensive attention in the field of regenerative medicine.It has been reported that the abnormal expression of Sox2 in various human tissues promotes the differentiation of mature somatic cells into stem cells,and participates in the malignant proliferation,invasion and metastasis of various tumors,including lung cancer,breast cancer and prostate cancer,through cascade amplification effect.Sox2 is regarded as a "carcinogenic transcription factor".However,the study of Sox2 in kidney tissue is less.At the same time,it was found that Sox2 could act as a pattern recognition receptor when the organism was infected,directly recognize foreign bacterial DNA through its high mobility group protein(HMG)domain,and participate in the innate immune response of the organism.This breakthrough discovery provides a preliminary clue for Sox2's possible involvement in the pathogenesis of immune diseases.AAV is a rapidly progressing autoimmune disease.So far,no reports about Sox2 in AAV have been found.This study preliminarily analyzed the expression of Sox2 in kidney tissues of AAV patients,and discussed the possible pathogenic link of Sox2 in AAV,which provided a preliminary basis for further exploring the possible pathogenic link of AAV.Method:Eleven renal tissue samples of hospitalized patients diagnosed as AAV with renal biopsy by the nephrology department of Xinqiao hospital,Army Medical University from February 2012 to March 2018 were included in this study.Clinical data of the patients were collected through the electronic medical record system.Diagnostic criteria for AAV is the same as the former.Seven normal renal samples adjacent to renal cancer of patients in the urological department of the same hospital were collected as control group.The expression of Sox2 in both groups was detected by immunohistochemistry.The co-expression of Sox2 and Claudin 1,a marker of glomerular parietal epithelial cells,were detected by double immunofluorescence staining,and the correlation between Sox2 and clinical indicators were analyzed.Result:1.The expression level of Sox2 in the renal tissue of AAV patients was significantly higher than that of normal group(P=0.002);2.Double immunofluorescence staining showed that Sox2 was co-expressed with Claudin 1,a marker of glomerular parietal epithelial cells,in the cellular crescent.;3.Correlation analysis showed that Sox2 expression in renal tissue was positively correlated with D-dimer(r=0.780,P=0.039),IL-6(r=0.877,P=0.004),CRP(r=0.910,P=0.002)and ESR(r=0.669,P=0.034).Conclusion:1.The level of Sox2 in renal tissue was positively correlated with ESR,CRP,IL-6 and D-dimer levels,suggesting its role in disease activity.2.Sox2 may promote the formation of crescents by regulating the activation of PECs.